Gina R. Petroni

Randomized Comparison of ABVD and MOPP/ABV Hybrid for the Treatment of Advanced Hodgkin’s Disease: Report of an Intergroup Trial

PURPOSE In a series of trials, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP/ABV) have been identified as effective treatments for Hodgkins disease. We compared these regimens as initial chemotherapy for Hodgkins disease. PATIENTS AND METHODS Adult patients (N = 856) with advanced Hodgkins disease were randomly assigned to treatment with ABVD or MOPP/ABV. The major end points were failure-free and overall survival, life-threatening acute toxicities, and serious long-term toxicities, including cardiomyopathy, pulmonary toxicity, myelodysplastic syndromes (MDS), and secondary malignancies. RESULTS The rates of complete remission (76% v 80%, P =.16), failure-free survival at 5 years (63% v 66%, P =.42), and overall survival at 5 years (82% v 81%, P =.82) were similar for ABVD and MOPP/ABV, respectively. Clinically significant acute pulmonary and hematologic toxicity were more common with MOPP/ABV (P =.060 and.001, respectively). There was no difference in cardiac toxicity. There were 24 deaths attributed to initial treatment: nine with ABVD and 15 with MOPP/ABV (P =.057). There have been 18 second malignancies associated with ABVD and 28 associated with MOPP/ABV (P =.13). Thirteen patients have developed MDS or acute leukemia: 11 were initially treated with MOPP/ABV, and two were initially treated with ABVD but subsequently received MOPP-containing regimens and radiotherapy before developing leukemia (P =.011). CONCLUSION ABVD and the MOPP/ABV hybrid are effective therapies for Hodgkins disease. MOPP/ABV is associated with a greater incidence of acute toxicity, MDS, and leukemia. ABVD should be considered the standard regimen for treatment of advanced Hodgkins disease.

Clinical and Immunologic Results of a Randomized Phase II Trial of Vaccination Using Four Melanoma Peptides Either Administered in Granulocyte-Macrophage Colony-Stimulating Factor in Adjuvant or Pulsed on Dendritic Cells

PURPOSE To determine clinical and immunologic responses to a multipeptide melanoma vaccine regimen, a randomized phase II trial was performed. PATIENTS AND METHODS Twenty-six patients with advanced melanoma were randomly assigned to vaccination with a mixture of four gp100 and tyrosinase peptides restricted by HLA-A1, HLA-A2, and HLA-A3, plus a tetanus helper peptide, either in an emulsion with granulocyte-macrophage colony-stimulating factor (GM-CSF) and Montanide ISA-51 adjuvant (Seppic Inc, Fairfield, NJ), or pulsed on monocyte-derived dendritic cells (DCs). Systemic low-dose interleukin-2 (Chiron, Emeryville, CA) was given to both groups. T-lymphocyte responses were assessed, by interferon gamma ELIspot assay (Chiron, Emeryville, CA), in peripheral-blood lymphocytes (PBLs) and in a lymph node draining a vaccine site (sentinel immunized node [SIN]). RESULTS In patients vaccinated with GM-CSF in adjuvant, T-cell responses to melanoma peptides were observed in 42% of PBLs and 80% of SINs, but in patients vaccinated with DCs, they were observed in only 11% and 13%, respectively. The overall immune response was greater in the GM-CSF arm (P <.02). Vitiligo developed in two of 13 patients in the GM-CSF arm but in no patients in the DC arm. Helper T-cell responses to the tetanus peptide were detected in PBLs after vaccination and correlated with T-cell reactivity to the melanoma peptides. Objective clinical responses were observed in two patients in the GM-CSF arm and one patient in the DC arm. Stable disease was observed in two patients in the GM-CSF arm and one patient in the DC arm. CONCLUSION The high frequency of cytotoxic T-lymphocyte responses and the occurrence of clinical tumor regressions support continued investigation of multipeptide vaccines administered with GM-CSF in adjuvant.

A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer.

Fifty-four patients with advanced breast cancer who had failed prior non-anthracycline combination chemotherapy were randomized to treatment with either epirubicin 85 mg/m2 or doxorubicin 60 mg/m2 intravenously every three weeks. Of 52 evaluable patients, 25% (six of 24) treated with epirubicin, and 25% (seven of 28) treated with doxorubicin experienced major therapeutic responses. The median duration of response to epirubicin was 11.9 months compared to 7.1 months with doxorubicin. Cardiotoxicity was monitored by serial multigated radionuclide cineangiocardiography performed at rest and after exercise. Laboratory evidence of cardiotoxicity was defined as a decrease in resting left ventricular ejection fraction of greater than 10% from the baseline value, or a decrease of 5% or greater with exercise compared with the resting study performed on the same day. Fifteen patients treated with epirubicin and 18 patients treated with doxorubicin had at least two determinations of left ventricular ejection fraction and were evaluable for laboratory cardiotoxicity. Using methods of survival analysis, the median doses to the development of laboratory cardiotoxicity were estimated to be 935 mg/m2 of epirubicin and 468 mg/m2 of doxorubicin. Four patients treated with epirubicin and five treated with doxorubicin developed symptomatic congestive heart failure. The median cumulative dose at which congestive heart failure occurred was 1,134 mg/m2 of epirubicin compared with 492 mg/m2 of doxorubicin. Fewer episodes of nausea and vomiting were observed in patients receiving epirubicin. Epirubicin is a new anthracycline with reduced cardiac toxicity, but preserved efficacy in the treatment of patients with advanced breast cancer.

Origin of Microsatellite Instability in Gastric Cancer

Microsatellite instability (MSI) is observed in 13-44% of gastric carcinoma. The etiology of MSI in gastric carcinoma has not been clearly defined. To assess the role of mismatch repair in the development of MSI in gastric cancer, expression of hMSH2 and hMLH1 was explored. We examined 117 gastric carcinomas for MSI and observed instability at one or more loci in 19 (16%) of these tumors. Of the 19 tumors with MSI, nine exhibited low-rate MSI (MSI-L) with instability at <17% of loci, whereas the remaining 10 exhibited high-rate MSI (MSI-H) with instability at >33% of loci examined. Immunohistochemical staining for hMLH1 and hMSH2 was performed on eight of the tumors with MSI-H, five with MSI-L, and 15 tumors without MSI. All eight tumors with MSI-H showed loss of staining for either hMLH1 (n = 5) or hMSH2 (n = 3). In contrast, tumors with MSI-L or without MSI all showed normal hMSH2 and hMLH1 protein expression patterns. Moreover, all eight of the tumors with MSI-H also showed instability at BAT-26, whereas none of the MSI-L tumors or tumors without instability showed instability at BAT-26. These findings suggest that the majority of high-level MSI in gastric cancer is associated with defects of the mismatch repair pathway. Although larger studies are needed, BAT-26 appears to be a sensitive and specific marker for the MSI-H phenotype in gastric carcinoma.

Immunologic and Clinical Outcomes of Vaccination With a Multiepitope Melanoma Peptide Vaccine Plus Low-Dose Interleukin-2 Administered Either Concurrently or on a Delayed Schedule

PURPOSE A phase II trial was performed to test whether systemic low-dose interleukin-2 (IL-2) augments T-cell immune responses to a multipeptide melanoma vaccine. Forty patients with resected stage IIB-IV melanoma were randomly assigned to vaccination with four gp100- and tyrosinase-derived peptides restricted by human leukocyte antigen (HLA) -A1, HLA-A2, and HLA-A3, and a tetanus helper peptide plus IL-2 administered daily either beginning day 7 (group 1), or beginning day 28 (group 2). PATIENTS AND METHODS T-cell responses were assessed by an interferon gamma ELIspot assay in peripheral blood lymphocytes (PBL) and in a lymph node draining a vaccination site (sentinel immunized node [SIN]). Patients were followed for disease-free and overall survival. RESULTS T-cell responses to the melanoma peptides were observed in 37% of PBL and 38% of SINs in group 1, and in 53% of PBL and 83% of SINs in group 2. The magnitude of T-cell response was higher in group 2. The tyrosinase peptides DAEKSDICTDEY and YMDGTMSQV were more immunogenic than the gp100 peptides YLEPGPVTA and ALLAVGATK. T-cell responses were detected in the SINs more frequently, and with higher magnitude, than responses in the PBL. Disease-free survival estimates at 2 years were 39% (95% CI, 18% to 61%) for group 1, and 50% (95% CI, 28% to 72%) for group 2 (P = .32). CONCLUSION The results of this study support the safety and immunogenicity of a vaccine composed of four peptides derived from gp100 and tyrosinase. The low-dose IL-2 regimen used for group 1 paradoxically diminishes the magnitude and frequency of cytotoxic T lymphocyte responses to these peptides.

Effect of Granulocyte/Macrophage Colony-Stimulating Factor on Circulating CD8+ and CD4+ T-Cell Responses to a Multipeptide Melanoma Vaccine: Outcome of a Multicenter Randomized Trial

Purpose: Granulocyte/macrophage colony-stimulating factor (GM-CSF) administered locally together with vaccines can augment T-cell responses in animal models. Human experience has been limited to small and uncontrolled trials. Thus, a multicenter randomized phase II trial was done to determine whether local administration of GM-CSF augments immunogenicity of a multipeptide vaccine. It also assessed immunogenicity of administration in one versus two vaccine sites. Experimental Design: One hundred twenty-one eligible patients with resected stage IIB to IV melanoma were vaccinated with 12 MHC class Irestricted melanoma peptides to stimulate CD8+ T cells plus a HLA-DRrestricted tetanus helper peptide to stimulate CD4+ T cells, emulsified in incomplete Freunds adjuvant, with or without 110 g GM-CSF. Among 119 evaluable patients, T-cell responses were assessed by IFN- ELIspot assay and tetramer analysis. Clinical outcomes were recorded. Results: CD8+ T-cell response rates to the 12 MHC class Irestricted melanoma peptides (by day 50) with or without GM-CSF were 34 and 73, respectively (P < 0.001), by direct ELIspot assay. Tetramer analyses corroborated the functional data. CD4+ T-cell responses to tetanus helper peptide were higher without GM-CSF (95 versus 77; P = 0.005). There was no significant difference by number of vaccine sites. Three-year overall and disease-free survival estimates (95 confidence interval) were 76 (67-83) and 52 (43-61), respectively, with too few events to assess differences by study group. Conclusions: High immune response rates for this multipeptide vaccine were achieved, but CD8+ and CD4+ T-cell responses were lower when administered with GM-CSF. These data challenge the value of local GM-CSF as a vaccine adjuvant in humans. (Clin Cancer Res 2009;15(22):703644)

Immunologic and clinical outcomes of a randomized phase II trial of two multipeptide vaccines for melanoma in the adjuvant setting.

Purpose: Human melanoma cells express shared antigens recognized by CD8+ T lymphocytes, the most common of which are melanocytic differentiation proteins and cancer-testis antigens. However, peptide vaccines for melanoma usually target only one or two MHC class I–associated peptide antigens. Because melanomas commonly evade immune recognition by selective antigen loss, optimization of melanoma vaccines may require development of more complex multipeptide vaccines. Experimental Design: In a prospective randomized clinical trial, we have evaluated the safety and immunogenicity of a vaccine containing a mixture of 12 peptides from melanocytic differentiation proteins and cancer-testis antigens, designed for human leukocyte antigen types that represent 80% of the melanoma patient population. This was compared with a four-peptide vaccine with only melanocytic differentiation peptides. Immune responses were assessed in peripheral blood and in vaccine-draining lymph nodes. Results: These data show that (a) the 12-peptide mixture is immunogenic in all treated patients; (b) immunogenicity of individual peptides is maintained despite competition with additional peptides for binding to MHC molecules; (c) a broader and more robust immune response is induced by vaccination with the more complex 12-peptide mixture; and (d) clinical outcome in this peptide vaccine trial correlates with immune responses measured in the peripheral blood lymphocytes. Conclusions: These data support continued investigation of complex multipeptide vaccines for melanoma.

Primary Central Nervous System Post-Transplantation Lymphoproliferative Disorder: An International Primary Central Nervous System Lymphoma Collaborative Group Report

Primary central nervous system (CNS) post‐transplantation lymphoproliferative disorder (PCNS‐PTLD) is a rare complication of solid organ transplantation. The objectives of this study were to define the clinical, radiologic, and pathologic features of this disease and to explore the impact of treatment on patient outcomes.

Prognostic factors in advanced ovarian carcinoma.

Nineteen factors were analyzed for prognostic significance in a series of 89 women with advanced (stage III or IV) ovarian carcinoma treated with chemotherapy after initial debulking surgery. Seventy-eight of these women received cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, Ohio), and cisplatin (CAP) treatment, and 11 received cyclophosphamide initially with Adriamycin and cisplatin administered at the time of recurrence. Median survival and remission duration were 25 and 19 months, respectively. Using survival as an end point, significant prognostic factors in univariate analyses included the total residual mass after debulking (P = .0007), largest residual mass after debulking (P = .0008), and stage (P = .0098). Using remission duration as an end point, significant prognostic factors in univariate analyses included total residual mass after debulking (P = .007) and the largest residual mass after debulking (P = .0020). The prognostic variables were then considered as possible predictors of survival in a multivariate analysis using the Cox proportional hazards model resulting in the following expression: lambda i(t)/lambda o(t) = exp(0.5928 (log TRM - 1.8117) + 0.6450 (stage - 0.3827) + 0.6673 (C4 - 0.4198) - 0.8596 (CAP - 0.8642)), where lambda i(t)/lambda o(t) is the risk of dying for a particular patient compared with the average risk of the entire group; log TRM is the log of the volume of the total residual mass in cm3 plus 1.0; stage = 0 if stage III, 1 if stage IV; C4 = 0 if cytologic grade is 1, 2, or 3 and 1 if grade 4; CAP = 0 if treatment is cyclophosphamide and 1 if CAP. Median survival times of patients with relative risk greater than 1 and less than 1 are 43 and 19 months respectively. If this model is confirmed in a prospective study, then it could be used to assign risk and assess treatment options for similar patients at diagnosis.

Evaluation of peptide vaccine immunogenicity in draining lymph nodes and peripheral blood of melanoma patients

Many peptide epitopes for cytotoxic T lymphocytes (CTLs) have been identified from melanocytic differentiation proteins. Vaccine trials with these peptides have been limited mostly to those associated with HLA‐A2, and immune responses have been detected inconsistently. Cases of clinical regression have been observed after peptide vaccination in some trials, but melanoma regressions have not correlated well with T‐cell responses measured in peripheral blood lymphocytes (PBLs). We vaccinated stage IV melanoma patients with a mixture of gp100 and tyrosinase peptides restricted by HLA‐A1 (DAEKSDICTDEY), HLA‐A2 (YLEPGPVTA and YMDGTMSQV) and HLA‐A3 (ALLAVGATK) in an emulsion with GM‐CSF and Montanide ISA‐51 adjuvant. CTL responses were assessed in PBLs and in a lymph node draining a vaccine site (sentinel immunized node, SIN). We found CTL responses to vaccinating peptides in the SIN in 5/5 patients (100%). Equivalent assays detected peptide‐reactive CTLs in PBLs of 2 of these 5 patients (40%). CTLs expanded from the SIN lysed melanoma cells naturally expressing tyrosinase or gp100. We demonstrated immunogenicity for peptides restricted by HLA‐A1 and ‐A3 and for 1 HLA‐A2 restricted peptide, YMDGTMSQV. Immune monitoring of clinical trials by evaluation of PBLs alone may under‐estimate immunogenicity; evaluation of SIN provides a new and sensitive approach for defining responses to tumor vaccines and correlating these responses with clinical outcomes. This combination of an immunogenic vaccine strategy with a sensitive analysis of CTL responses demonstrates the potential for inducing and detecting anti‐tumor immune responses in the majority of melanoma patients.